Simvastatin Attenuates Areca Nut Extract-Induced Subdermal Fibrosis in Mice by Targeting TGF-ß Signaling Pathways.

Oral submucous fibrosis (OSMF) is a chronic inflammatory disease and a potentially malignant oral disorder, characterized by fibrosis of the oral mucosa. TGF-ß signaling pathways have been implicated in the development of OSMF, with areca nut extract (ANE) contributing to the disease progression. Simvastatin, a statin drug, has demonstrated anti-fibrotic properties in various fibrotic conditions. However, its therapeutic potential in treating OSMF remains unclear. In this study, 8-week-old male BALB/c mice were randomly divided into three groups based on different time points. Each mouse was then treated with four different drug formulations. Post-treatment, specimens were collected for histopathological examination and staining to assess skin thickness, fibrosis, and collagen deposition. ANE treatment alone significantly increased skin thickness and collagen deposition compared to the control group after the 4-week time point. The combined administration of ANE and simvastatin, resulted in a notable reduction in skin thickness and collagen deposition. Western blot analysis revealed that simvastatin effectively suppressed the expression of fibrosis-related proteins, including CTGF, and α-SMA, in ANE-induced subdermal fibrosis. These results suggest that simvastatin has potential therapeutic effects on ANE-induced subdermal fibrosis, providing a foundation for future studies and possible clinical applications.

Prevalence of Dental Anomalies in Taiwanese Children with Cleft Lip and Cleft Palate.

The aim of this study was to investigate the prevalence of tooth agenesis, tooth malformation, and eruption patterns of upper canines/first premolars in Taiwanese children. A total of 132 cleft lip and cleft palate (CLCP) patients (82 boys and 50 girls) underwent alveolar bone grafting (ABG) between 2012 and 2022. The patients' dental records and X-ray images were inspected. We examined dental anomalies, including congenital missing teeth, microdontia, and transposition from the upper canines to the upper first premolars in these CLCP patients. Additionally, we investigated the mean ABG operation age (9.27 ± 0.76 years) of our patient; 40.9% of them received pre-ABG orthodontic treatment at 8.72 ± 0.70 years. Among the 132 cleft subjects, the prevalence of tooth agenesis is 73.5% (97/132). The most frequently missing teeth are the maxillary lateral incisors (right side: 46.2%; left side: 47.0%). In this study, microdontia are found in all the upper incisors, of which the highest percentage (18.9%) is observed in the upper left lateral incisors. The prevalence of upper canine and first premolar transposition is 10.6%. The pattern of tooth agenesis and microdontia of the upper lateral incisors shows a strong correlation with the cleft sites of these CLCP patients in our study. These results may support the idea that the patterns of dental anomalies in CLCP patients are region-specific.

The early gene hhi1 reactivates Heliothis zea nudivirus 1 in latently infected cells.

Heliothis zea nudivirus 1 (HzNV-1), previously known as Hz-1 virus, is an insect virus able to establish both productive and latent infections in several lepidopteran insect cells. Here, we have cloned and characterized one of the HzNV-1 early genes, hhi1, which maps to the HindIII-I fragment of the viral genome. During the productive viral infection, a 6.2-kb hhi1 transcript was detectable as early as 0.5 h postinfection (hpi). The level of transcript reached a maximum at 2 hpi and gradually decreased after 4 hpi. The transcript was not detectable during the latent phase of viral infection. Upon cycloheximide treatment, much higher levels of hhi1 transcript were detected throughout the productive viral infection cycle, suggesting that newly synthesized proteins are not needed for the expression of hhi1. Nevertheless, viral coinfection can further stimulate the expression of transfected hhi1 promoter in a plasmid. Transient hhi1 expression in latently infected cells resulted in a significant increase in virus titer and viral DNA propagation, suggesting that hhi1 plays a critical role in viral reactivation. Additional experiments showed that six early genes, which possibly function in transcription or DNA replication, were activated in the latent cells upon hhi1 transfection. Among these six genes, orf90 and orf121 expression could be induced by hhi1 alone without the need for other viral genes. Our discovery should be useful for future mechanistic study of the switches of latent/productive HzNV-1 viral infections.

Malignant development in patients with oral potentially malignant disorders detected through nationwide screening: Outcomes of 5-year follow-up at a single hospital.

BACKGROUND: Although survival rate and quality of life are improved if patients with oral carcinoma can be detected early, however, such lesions are usually asymptomatic; therefore, it is hard to raise awareness. Screening has proved to be cost-effective for early detection. METHODS: Sixty-two patients with oral carcinomas and 555 patients with oral potentially malignant disorders (OPMDs) who were detected through screening were examined the relationship between clinicopathological features and follow-up outcomes. RESULTS: The 5-year cumulative cancer-free interval rate was 94.1%, and the annual malignant transformation rate was 1.16%. The rate of interval carcinoma development from Candida hyperplasia, oral submucous fibrosis, homogeneous leukoplakia, non-homogenous leukoplakia, and verrucous hyperplasia, was 13.6%, 5.7%, 4.6%, 12.1%, and 21.3%, respectively. Significant independent risk factors for interval carcinoma development were heavy betel quid chewing, verrucous hyperplasia, and surgery refusal. CONCLUSIONS: Well-designed risk assessment, treatment, and surveillance program could lead to earlier cancer detection and thereby reduce mortality and morbidity.

Risk analysis of malignant potential of oral verrucous hyperplasia: A follow-up study of 269 patients and copy number variation analysis.

BACKGROUND: Oral verrucous hyperplasia is commonly observed in the oral cavity of betel quid chewers and is a potential malignant disorder. However, the prognostic factors and genetic alterations of oral verrucous hyperplasia are unclear. METHODS: We calculate the survival rate and prognostic factors using a Kaplan-Meier analysis and Cox proportional hazards regression model. Copy number variations were analyzed using a single-nucleotide polymorphism (SNP) array. RESULTS: The 5-year disease-free and cancer-free survival rates of patients with oral verrucous hyperplasia were approximately 40% and 70%, respectively. Heavy betel quid chewing, advanced oral submucous fibrosis, and nonbuccal and nontongue lesions were risk factors for malignant transformation, whereas dysplasia did not affect outcomes. The gene amplification of CTTN, FOLR3, ORAOV1, PPFIA1, and RNF121 were associated with the poor prognosis of oral verrucous hyperplasia. CONCLUSION: Heavy betel quid chewing, advanced oral submucous fibrosis, and nonbuccal and nontongue lesions are high-risk factors of patients with oral verrucous hyperplasia. The 5-copy number variation-associated genes could be used for early diagnosis and predicting the prognosis.

p22phox confers resistance to cisplatin, by blocking its entry into the nucleus.

Cisplatin (CDDP) is a potent chemotherapeutic agent but resistance to the drug remains a major challenge in cancer treatment. To evaluate the efficacy of CDDP in oral squamous cell carcinoma (OSCC), we found that p22phox was highly expressed in CDDP-resistant OSCC specimens. Knockdown of p22phox sensitized OSCC cell lines to CDDP (P < 0.05). Stable overexpression of p22phox augmented CDDP resistance, as evidenced by the significantly higher IC50 values. This cytoprotective effect was attributed to the abrogation of CDDP-induced apoptosis. Akt phosphorylation was increased in p22phox stable lines. However, blocking PI3K/Akt pathway only partially restored CDDP-induced apoptosis. In addition, the overexpressed p22phox in OSCC cells exhibited cytoplasmic localization with enhanced perinuclear expression, consistent with the localization pattern in OSCC specimens. Remarkably, CDDP entry into the nucleus was severely impaired in p22phox-overexpressing cells (P < 0.001), and cytoplasmically accumulated CDDP was co-localized with overexpressed p22phox. This was supported by decreased CDDP-DNA adduct formation and delayed chk1-p53 signaling activation. Together, overexpression of p22phox sequestered CDDP and caused defective CDDP entry into the nucleus, significantly attenuating CDDP-induced apoptosis. Such diminished apoptosis was further abolished by p22phox-activating PI3K/Akt pathway. Our work has suggested a novel biomarker and insight into the mechanism of CDDP resistance.

Sprouty2 protein is downregulated in human squamous cell carcinoma of the head and neck and suppresses cell proliferation in vitro.

Sprouty2 is known for its tumor-suppressing effect in various human malignant diseases. In head and neck squamous cell carcinoma (HNSCC), the role of sprouty2 in tumorigenesis and clinical implication remains elusive. The aim of the present study was to investigate the expression of sprouty2 in patients with HNSCC and its function in vitro. Quantitative analysis of mRNA expression of sprouty2 was performed on frozen tumor samples from 42 patients with HNSCC and 19 with oral verrucous hyperplasia (OVH) with paired counterparts of normal mucosa. Downregulation of sprouty2 expression was demonstrated in 79% of HNSCC samples and in 58% of OVH samples compared with paired samples of normal mucosa. Enhanced expression of sprouty2 protein suppressed the growth of HNSCC cells and signaling of the phosphorylated AKT pathway. Following transfection of the sprouty2 plasmid, HNSCC cells were more sensitive to sorafenib, a tyrosine kinase inhibitor of Raf and vascular endothelial growth factor receptor. The present study suggested that sprouty2 expression was downregulated and behaved as a tumor suppressor in HNSCC. Sprouty2 expression in tumor cells enhanced sensitivity to sorafenib. Further studies are required to define the clinical impact of sprouty2 in patients with HNSCC.